Reshaping the brain: scientists reprogram neurons after birth

Altered neurons link up to a different brain region.

The cerebral cortex—the gray matter that forms the outer layers of the mammalian cerebrum and cerebellum—is divided into six different layers based on the presence of specialized neurons, and we've known that since the early 1900s. Denis Jabaudon is interested in using the tools of modern biology to understand the genetic mechanisms that establish and maintain those layers. Over the past few years, his lab has published papers implicating various genes in the generation of specific neuronal subtypes.

Now they have gone a step further. They have developed a new electrochemical method to transfer genes into specific types of neurons—they call it iontoporation. Using it, they have transformed one type of neuron in a mature brain into a different type entirely. (Imagine a lightning bolt and crash of thunder here to indicate how momentous and scary this is.) Just kidding—it’s not actually scary. Instead, it tells us something about the ability of a mature brain to adapt to being rewired.

Although Jabaudon and others have made some headway in working out how the different neurons arise, they still don’t know how plastic they are—if they can change fates after they started differentiating down one particular path. In the context of brain injury, it would be useful to know if certain neural circuits could be reprogrammed and repaired by having the neurons that are already present change fates to adapt to the damage. But this has been challenging to determine, because changing the fate of specific neurons in the latter stages of differentiation has been technically difficult.

Layer 4 mouse spiny neurons have round bodies, with many short dendrites (connections with other cells) that stay within their layer of the brain. They receive sensory signals from the thalamus. Layer 5B output neurons are pyramidal in shape, with a prominent dendrite that extends all the way to layer 1.

Fezf2 is a transcription factor that regulates the activity of other genes. It is expressed throughout the L5B neuron’s entire life, and it is necessary and sufficient for turning early cortical cells into L5B neurons.

When Jabaudon’s colleagues iontoporated Fezf2 into L4 neurons the day after mice were born, a week after the neurons had established their identity, it completely transformed them. You guessed it: the L4 neurons walked, talked, looked, and quacked just like L5B neurons. They looked like L5B's and began transmitting signals to other nerves just as these cells did. Most significantly, however, they rearranged their intracortical inputs, meaning that they now received signals from layer 2/3 neurons instead of from the thalamus.

The researchers tried their iontoporation as late as ten days after the mice were born, and found that the neurons become less amenable to reprogramming with time, but some features were still malleable for a week after the mice were born—two weeks after the neurons originated.

The authors hope to further explore the molecular mechanisms responsible for the emergence and patterning of different cortical areas during brain development and their plasticity after injury. They hope that one day, reprogramming existing neurons could be a means of nervous system repair.